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Docking studies play a critical role in the current workflow of drug discovery. However, limitations may often arise through factors including inadequate ligand sampling, a lack of protein flexibility, scoring function inadequacies (e.g., due to metals, co‐factors, etc.), and difficulty in retaining explicit water molecules. Herein, we present a novel CHARMM‐based induced fit docking (CIFDock) workflow that can circumvent these limitations by employing all‐atom force fields coupled to enhanced sampling molecular dynamics procedures. Self‐guided Langevin dynamics simulations are used to effectively sample relevant ligand conformations, side chain orientations, crystal water positions, and active site residue motion. Protein flexibility is further enhanced by dynamic sampling of side chain orientations using an expandable rotamer library. Steps in the procedure consisting of fixing individual components (e.g., the ligand) while sampling the other components (e.g., the residues in the active site of the protein) allow for the complex to adapt to conformational changes. Ultimately, all components of the complex—the protein, ligand, and waters—are sampled simultaneously and unrestrained with SGLD to capture any induced fit effects. This modular flexible docking procedure is automated using CHARMM scripting, interfaced with SLURM array processing, and parallelized to use the desired number of processors. We validated the CIFDock procedure by performing cross‐docking studies using a data set comprised of 21 pharmaceutically relevant proteins. Five variants of the CHARMM‐based SWISSDOCK scoring functions were created to quantify the results of the final generated poses. Results obtained were comparable to, or in some cases improved upon, commercial docking program data. [ABSTRACT FROM AUTHOR]

A new vibrational subsystem analysis (VSA) method is presented for coupling global motion to a local subsystem while including the inertial effects of the environment. The premise of the VSA method is a partitioning of a system into a smaller region of interest and a usually larger part referred to as environment. This method allows the investigation of local-global coupling, a more accurate estimation of vibrational free energy contribution for parts of a large system, and the elimination of the “tip effect” in elastic network model calculations. Additionally, the VSA method can be used as a probe of specific degrees of freedom that may contribute to free energy differences. The VSA approach can be employed in many ways, but it will likely be most useful for estimating activation free energies in QM/MM reaction path calculations. Four examples are presented to demonstrate the utility of this method. [ABSTRACT FROM AUTHOR]

Use of quantum mechanical/molecular mechanical (QM/MM) methods in binding free energy calculations, particularly in the SAMPL challenge, often fail to achieve improvement over standard additive (MM) force fields. Frequently, the implementation is through use of reference potentials, or the so-called “indirect approach”, and inherently relies on sufficient overlap existing between MM and QM/MM configurational spaces. This overlap is generally poor, particularly for the use of free energy perturbation to perform the MM to QM/MM free energy correction at the end states of interest (e.g., bound and unbound states). However, by utilizing MM parameters that best reproduce forces obtained at the desired QM level of theory, it is possible to lessen the configurational disparity between MM and QM/MM. To this end, we sought to use force matching to generate MM parameters for the SAMPL6 CB[8] host-guest binding challenge, classically compute binding free energies, and apply energetic end state corrections to obtain QM/MM binding free energy differences. For the standard set of 11 molecules and the bonus set (including three additional challenge molecules), error statistics, such as the root mean square deviation (RMSE) were moderately poor (5.5 and 5.4 kcal/mol). Correlation statistics, however, were in the top two for both standard and bonus set submissions (R2 of 0.42 and 0.26, τ of 0.64 and 0.47 respectively). High RMSE and moderate correlation strongly indicated the presence of systematic error. Identifiable issues were ameliorated for two of the guest molecules, resulting in a reduction of error and pointing to strong prospects for the future use of this methodology. [ABSTRACT FROM AUTHOR]

Indirect (S)QM/MM free energy simulations (FES) are vital to efficiently incorporating sufficient sampling and accurate (QM) energetic evaluations when estimating free energies of practical/experimental interest. Connecting between levels of theory, i.e., calculating Δ A l o w → h i g h , remains to be the most challenging step within an indirect FES protocol. To improve calculations of Δ A l o w → h i g h , we must: (1) compare the performance of all FES methods currently available; and (2) compile and maintain datasets of Δ A l o w → h i g h calculated for a wide-variety of molecules so that future practitioners may replicate or improve upon the current state-of-the-art. Towards these two aims, we introduce a new dataset, "HiPen", which tabulates Δ A g a s M M → 3 o b (the free energy associated with switching from an M M to an S C C − D F T B molecular description using the 3ob parameter set in gas phase), calculated for 22 drug-like small molecules. We compare the calculation of this value using free energy perturbation, Bennett's acceptance ratio, Jarzynski's equation, and Crooks' equation. We also predict the reliability of each calculated Δ A g a s M M → 3 o b by evaluating several convergence criteria including sample size hysteresis, overlap statistics, and bias metric (Π). Within the total dataset, three distinct categories of molecules emerge: the "good" molecules, for which we can obtain converged Δ A g a s M M → 3 o b using Jarzynski's equation; "bad" molecules which require Crooks' equation to obtain a converged Δ A g a s M M → 3 o b ; and "ugly" molecules for which we cannot obtain reliably converged Δ A g a s M M → 3 o b with either Jarzynski's or Crooks' equations. We discuss, in depth, results from several example molecules in each of these categories and describe how dihedral discrepancies between levels of theory cause convergence failures even for these gas phase free energy simulations. [ABSTRACT FROM AUTHOR]

The effective description of molecular geometry is important for theoretical studies of intermolecular interactions. Here we introduce a new translation-rotation-internal coordinate (TRIC) system which explicitly includes the collective translations and rotations of molecules, or parts of molecules such as monomers or ligands, as degrees of freedom. The translations are described as the centroid position and the orientations are represented with the exponential map parameterization of quaternions. When TRIC is incorporated into geometry optimization calculations, the performance is consistently superior to existing coordinate systems for a diverse set of systems including water clusters, organic semiconductor donor-acceptor complexes, and small proteins, all of which are characterized by nontrivial intermolecular interactions. The method also introduces a new way to scan the molecular orientations while allowing orthogonal degrees of freedom to relax. Our findings indicate that an explicit description of molecular translation and rotation is a natural way to traverse the many-dimensional potential energy surface. [ABSTRACT FROM AUTHOR]